High levels of blood glucose are thought to be associated with colorectal cancer (CRC) and hyperinsulinemia, an interstage in the development of CRC. The purpose of this study was to examine associations between incident CRC and blood glucose; plasma insulin; and the homeostasis model assessment for insulin resistance (HOMA2-IR), respectively, and to determine whether these associations were dependent on sex and cancer site.
Trang 1R E S E A R C H A R T I C L E Open Access
High blood glucose levels are associated
with higher risk of colon cancer in men: a
cohort study
Alexandra Vulcan1* , Jonas Manjer2and Bodil Ohlsson3
Abstract
Background: High levels of blood glucose are thought to be associated with colorectal cancer (CRC) and
hyperinsulinemia, an interstage in the development of CRC The purpose of this study was to examine associations between incident CRC and blood glucose; plasma insulin; and the homeostasis model assessment for insulin resistance (HOMA2-IR), respectively, and to determine whether these associations were dependent on sex and cancer site
Methods: The Malmö Diet and Cancer cardiovascular cohort comprises 6103 individuals During 81,781 person-years of follow-up, 145 cases of CRC were identified The hazard ratio of measured blood glucose and plasma insulin and
calculated HOMA2-IR were estimated with Cox proportional hazard regression
Results: An association was found between high levels of blood glucose and risk of CRC (HR: 1.72 for the highest
was not found in women No associations between plasma insulin, or HOMA2-IR, and CRC, were found
Conclusion: High levels of blood glucose in men are associated with risk of colon cancer The findings contribute to facilitating to identify those most in need of prevention and screening
Keywords: Blood glucose, Colorectal cancer (CRC), Homeostasis model assessment of insulin resistance (HOMA2-IR), Malmö diet and cancer study, Plasma insulin, Sex
Background
Colorectal cancer (CRC) is one of the most common
cancer forms in the Western world [1] The increased
incidence of CRC is associated with the increased
incidence of lifestyle-related diseases, e.g., metabolic
syn-drome, overweight, obesity, and type 2 diabetes [2–4]
The latter diseases are characterized by hyperglycaemia,
hyperinsulinemia, and insulin resistance [5] The interaction
between these diseases and CRC is being discussed, and
molecular and etiological mechanisms are being sought
Hyperglycaemia might be associated with CRC [6], and the
association may differ depending on different cancer sites
and sex [4, 7] Involvement of reactive oxygen species (ROS) and the accumulation of advanced glycation end products (AGE) are hypothesized to stimulate carcinogenic pathways [8–10] Other proposals are that hyperinsuline-mia drives the carcinogenic process through influence on the growth of cancer cells, stimulation of proliferation, de-crease of apoptosis, and promotion of intestinal carcinogen-esis [11] Another hypothcarcinogen-esis is that insulin rcarcinogen-esistance is responsible for the increased cancer risk Although several studies have been conducted in the field, most of them have been case-control studies, and there has been discussion of whether further cohort studies are warranted [7]
Method The primary aim of this study was to examine the asso-ciations between incident CRC and blood glucose levels;
* Correspondence: alexandra.vulcan@med.lu.se
1 Lund University, Skåne University Hospital, Department of Clinical Sciences,
Division of Internal Medicine, Jan Waldenströms gata 14, 205 02 Malmö,
Sweden
Full list of author information is available at the end of the article
© The Author(s) 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver
Trang 2plasma insulin levels; and homeostasis model assessment
for insulin resistance (HOMA2-IR), respectively, and
incident CRC The secondary aim was to study whether
the associations were dependent on sex and cancer site
The study was approved by the Regional Ethical
Review Board in Lund (50–91, 2013/804)
Study population
The Malmö Diet and Cancer study (MDCS) is a large
population-based study, conducted in the period 1991–
1996 in Malmö, where all men and women, born between
1923 and 1950, were invited to participate Altogether,
28,098 participants completed the baseline examinations
after having given their written informed consent The
method of MDCS has previously been described by
Man-jer et al [12] The Malmö Diet and Cancer cardiovascular
cohort (MDC-CC) comprises 6103 individuals randomly
selected from MDCS Out of the 6103 participants in
MDC-CC, 5540 individuals accepted and were
re-scheduled for blood sampling 396 individuals did not
leave a blood glucose and plasma insulin sample and were
therefore excluded from the present study, leaving 5144
individuals (2117 men) From the remaining individuals,
prevalent diabetes was found in 219 individuals (123
men), and prevalent CRC in 14 individuals (2 men), at
baseline, all of whom were also excluded from the study,
leaving 4910 individuals (1992 men)
Cases of CRC
In the study, 145 cases of CRC (71 men) were identified
from the Swedish Cancer Registry, of which 81 cases
were colon cancer (37 men) and 64 were rectal cancer
(34 men), during 81,781 person-years of follow-up
Follow-up time was defined as the time from the date of
enrolment until the date of CRC diagnosis, death,
migra-tion or end of follow-up (31 December 2010), whichever
came first The mean follow-up was 16.7 ± 3.7 years
Plasma insulin, blood glucose and insulin resistance
In the MDC-CC all the blood and plasma samples were
collected at the MDC-CC baseline by a trained nurse in the
morning after 12 h of fasting, and plasma was separated
and immediately frozen at−20 °C until analysed Analyses
were performed according to the clinical routines of the
Department of Clinical Chemistry Blood glucose was
ana-lysed using a routine hexokinase method Insulin levels
were measured in mIU/ml by a radioimmunoassay The
lowest limit for detection was 3 mlU/ml
HOMA2-IR was calculated with the use of a HOMA2-IR
calculator [13] In the analysis of HOMA2-IR, extreme
values of blood glucose (< 3.5 or >25 mmol/l) were excluded,
as were extreme values of plasma insulin (< 3 or >57.5 mIU/
ml), thus leaving 4451 individuals for analysis of
HOMA2-IR From the remaining individuals 135 cases of CRC, 76 cases colon cancer, and 59 cases of rectal cancer were found
Other variables
At MDCS baseline, age was obtained from personal identification numbers Body Mass Index (BMI) was cal-culated from measured weight and length
A self-administered structured questionnaire was used for the assessment of level of education, physical activity, alcohol consumption and smoking The level of education was di-vided into four different categories: ≤ 8 years; 9–10 years; 11–13 years of education; and university degree The sub-jects were asked to estimate their physical activity in terms
of how many minutes per week they spent on 17 different activities The duration was multiplied with an activity-specific intensity coefficient and an overall leisure-time phys-ical activity score was created [14] Alcohol intake was di-vided into four categories: zero; < 15 g/d for women and
<20 g/d for men; 15–30 g/d for women and 20–40 g/d for men; and >30 g/d for women and >40 g/d for men Smokers were divided into three categories: current smokers; ex-smokers; and non-smokers Irregular smoking was counted
as current smoking The result was divided into quartiles Prevalent diabetes was determined by self-reported ill-ness based on physician’s diagnosis or treatment with anti-diabetes medicine, or information from medical data registries indicating a date of diagnosis before inclu-sion in the MDC-CC Incident diabetes diagnosis was obtained either from the Regional Diabetes 2000 register
of Scania, the Malmö HbA1C register or the Swedish National Diabetes Register until 31st of December 2010
In the MDC-CC, 716 incident cases of diabetes (350 men) were found In those with incident diabetes, 31 cases of incident CRC (22 men) were found
Statistics The SPSS statistics (version 23; IBM Corporation, Armonk, NY, USA) was used for all statistical analyses Chi-square test was used when examining baseline cat-egorical characteristics, and T-test when examining baseline continuous characteristics, in the cases and the non-cases
The Cox proportional hazard regression model was used when estimating hazard ratios (HR) of incident CRC, colon cancer, and rectal cancer, depending on quartiles of blood glucose, plasma insulin and HOMA2-IR The pro-portionality assumption was tested for all the adjustment factors with a Kaplan-Maier curve before analysis Two models are presented: an unadjusted model, and a full model The full model was adjusted for the background variables indicating a difference between the cases and the non-cases (p < 0.2), i.e age, sex (when appropriate), BMI, and smoking status
Trang 3A test for interaction between sex and blood glucose;
plasma insulin levels; and HOMA2-IR, respectively, with
regard to CRC incidence was performed by adding a
multiplicative variable (i.e sex × blood
glucose−/insu-lin-/HOMA2-IR quartiles (treated as continuous
vari-ables)) to the full model If a significant interaction was
found, subgroup analysis based on sex was performed
In the sensitivity analysis, we excluded individuals with
incident diabetes, and apart from that we made one
add-itional model, full model glucose/insulin The full model
insulin was only used when estimating HR for quartiles
of glucose and was adjusted for age, sex, BMI, smoking
status, and insulin The full model glucose was only used
when estimating HR for quartiles of insulin and adjusted
for age, sex, BMI, smoking status, and glucose In
addition, we excluded individuals with CRC diagnosis
within two years of inclusion
All tests were two-sided and statistical significance was
assumed atp < 0.05
Results
Compared with the non-cases, the cases were older
(Table 1), had larger waist circumference (86.9 ± 13.5 cm
and 83.2 ± 12.6 cm, respectively, p = 0.019), and higher
plasma insulin levels (9.6 ± 18.9 mIU/ml and 7.7 ± 7.1
mIU/ml, respectively, p = 0.012) at inclusion More of
the cases than non-cases developed diabetes during the
follow-up (21.4% and 14.6%, respectively)
Blood glucose levels and colorectal, colon, or rectal cancer
An association between high levels of blood glucose and
risk of CRC and colon cancer was found (HR: 1.72 for the
highest compared with the lowest quartile; 95% CI: 1.05,
2.84, p for trend = 0.044) and (HR: 1.70 for the highest
compared with the lowest quartile; 95% CI: 0.87, 3.33, p for
trend = 0.032) (Table 2), respectively With regard to blood
glucose levels, an interaction between sex was found in
CRC (p = 0.013) and in colon cancer (p = 0.032), but not in
rectal cancer (p = 0.130) A significant association between
high levels of blood glucose and CRC was found in men
(HR: 2.80 for the highest compared with the lowest quartile;
95% CI: 1.37, 5.70; p for trend = 0.001), but not in women
(HR: 1.02 for the highest compared with the lowest quartile;
95% CI: 0.53, 1.95; p for trend = 0.739) (Table 3) Also, a
sig-nificant association was found between high levels of blood
glucose and colon cancer in men (HR: 4.23 for the highest
compared with the lowest quartile; 95% CI: 1.46, 13.44; p
for trend = 0.002), but not in women (HR: 1.01 for the
high-est compared with the lowhigh-est quartile; 95% CI: 0.44, 2.34; p
for trend = 0.878) (Table 4)
Plasma insulin levels and colorectal, colon, or rectal cancer
No significant associations were found between plasma
insulin levels and CRC, colon, or rectal cancer (Table 2)
No interaction between sex and plasma insulin levels was found in CRC (p = 0.142), colon cancer (p = 0.358),
or in rectal cancer (p = 0.280)
Table 1 Baseline characteristics of cases and non-cases in the Malmö Diet and Cancer Study cardiovascular cohort
Cases
n = 145 (%) Non-casesn = 4765 (%) p-value
a
Body Mass Index (kg/ m 2
Body Mass Index ≤25 kg/m 2
- ≤ 25 kg/m 2
63 (43.4) 2356 (49.4)
- < 15 g/d for women and
<20 g/d for men
91 (62.8) 3088 (64.8)
- 15 –30 g/d for women and
- > 30 g/d for women and
>40 g/d for men
a
Calculated with Chi-square test for categorical variables and with T-test for the continuous variables
Physical activity was defined as high when in the highest quartile of the whole group, and lower when in the three lower quartiles [ 14 ]
Values are number of individuals and percentage or mean and standard deviation p < 0.05 was considered statistically significant
Trang 42 ,
2 ),
Trang 5HOMA2-IR and colorectal, colon, or rectal cancer
No significant associations between HOMA2-IR and
CRC, colon, or rectal cancer were found in the full
model (Table 2) There was a borderline interaction
be-tween sex and HOMA2-IR in CRC (p = 0.099), but not
in colon cancer (p = 0.211), or rectal cancer (p = 0.789) The associations between HOMA2-IR and CRC did not reach statistical significance in men (HR: 1.62 for the highest compared with the lowest quartile; 95% CI: 0.81, 3.25; p for trend = 0.132), or in women (HR: 0.77 for the
Table 3 Hazard ratio (HR) of incident colorectal- and colon cancer associated with blood glucose for men and women in the Malmö Diet and Cancer Study cardiovascular cohort
Colorectal cancer nmen = 1992 nwomen = 2981
Colon cancer nmen = 1958 nwomen = 2888
Quartiles of glucose Min-max (mIU/l) Cases/person-years HR 95% CI HR 95% CI Cases/person-years HR 95% CI HR 95% CI Men
2.90
1.25 0.55, 2.85
7.01
1.95 0.57, 6.70
4.45
2.03 0.95, 4.32
7.79
2 –08 0.60, 7.17
6.15
2.80 1.37, 5.70
15.87
4.23 1.46, 13.44
Women
2.38
1.21 0.62, 2.34
2.05
0.73 0.27, 1.96
1.66
0.82 0.44, 1.55
2.34
0.96 0.45, 2.09
2.17
1.02 0.53, 1.95
2.71
1.01 0.44, 2.34
Full model: Calculated with the Cox proportional hazard regression model Adjusted for age (quartiles of age), BMI (≤ 25 kg/m 2
, > 25 kg/m 2
), and smoking (current, ex or never) Values are quartile ranges, hazard ratios (HR), and 95% confidence intervals (CI)
Table 4 Hazard ratio (HR) of incident colorectal cancer associated with Homeostasis Model Assessment for Insulin Resistance (HOMA2-IR) for men and women in the Malmö Diet and Cancer Study cardiovascular cohort
Men ( n = 1824)
Women ( n = 2627)
HR was calculated with the Cox proportional hazard regression model
Unadjusted model: No adjustments made
Full model: Adjusted for age (quartiles of age), BMI (≤ 25 kg/m 2
, > 25 kg/m2), and smoking (current, ex or never)
Trang 6highest compared with the lowest quartile; 95% CI: 0.37,
1.59; p for trend = 0.779) (Table 4)
Sensitivity analysis
After excluding those with incident diabetes, the
associ-ation between blood glucose and CRC was no longer
significant (HR: 1.74 for the highest compared with the
lowest quartile; 95% CI: 1.00, 3.07, p for trend = 0.134)
The same was true for the association between blood
glucose and colon cancer (HR: 1.71 for the highest
com-pared with the lowest quartile; 95% CI: 0.80, 3.68, p for
trend = 0.128) In men, the association between blood
glucose and colon cancer had borderline significance
(HR: 3.47 for the highest compared with the lowest
quartile; 95% CI: 0.88, 13.74, p for trend = 0.099)
In excluding those with diagnosis of CRC within two
years from inclusion in the study (13 individuals, where of
eight were men), the association between blood glucose
and CRC had borderline significance (HR: 1.71 for the
highest compared with the lowest quartile; 95% CI: 1.01,
2.89, p for trend = 0.090), and the risk estimate for the
as-sociation between blood glucose and rectal cancer in men
increased (HR: 5.20 for the highest compared with the
lowest quartile; 95% CI: 1.47, 18.43, p for trend = 0.006)
In additionally adjusting for insulin in the full model
for glucose, neither the risk estimate, nor the
signifi-cance substantially changed Nor did they substantially
change when additionally adjusting for glucose in the
full model for insulin (data not shown)
Discussion
The results from the present study indicate that high
levels of blood glucose are associated with risk of CRC,
more specifically in men No associations were found for
insulin or HOMA2-IR and risk of CRC
Our results are in agreement with other studies, which
also found an association between high glucose levels
and CRC, with significant associations in men, but not
in women, and in colon cancer, but not in rectal cancer
[7] Glucose induces expressions of Amphiregulin,
through transcriptional regulation of the MAX-like
pro-tein X [15], suggesting that one part of the
tumorigen-esis in CRC might be glycolysis [16] Furthermore,
hyperglycaemia gives energy to malignant cells for their
proliferation [16], and thus favours cancer growth and
neoangiogenesis Since there can be an
insulin-independent glucose uptake in cancer cells, this may
have an impact on the association between glucose,
in-sulin and risk of CRC
In hyperglycaemia, the cells’ production of reactive
oxygen intermediates increases, and is therefore
specu-lated to be a part of the induction of apoptosis in
endo-thelial cells [17] Chronic inflammation, present for
example during hyperglycaemia, leads to imbalance
between production and restoration of ROS, leading to oxidative stress within the target tissue, which may dam-age DNA and reduce DNA repair [18]
Glucose and insulin levels are closely linked, which makes
it difficult to separate the association, although they influence the cancer development through different pathways Insulin stimulates the proliferation of cells partly through binding in-sulin to inin-sulin- or inin-sulin-like growth factor 1 (IGF-1) re-ceptors, and partly through inhibition of IGF-binding proteins, thus increasing the availability for IGF-1 to bind to IGF-1 receptors [19] Circulating IGF-1 is thought to in-crease the risk of CRC [20] In a meta-analysis by Xu et al [7], an association between plasma insulin levels and risk of CRC was found in case-cohort studies, but not in cohort studies, in line with the present cohort study
Insulin resistance, hyperinsulinemia, and hypergly-caemia are important factors in metabolic syndrome When insulin resistance develops in type 2 diabetes, the pancreatic insulin secretion is increased in compensation [21] It is speculated that excess of insulin might enhance colonic epithelial activity and induce the forma-tion of aberrant cryptic foci [22] Insulin resistance af-fects the metabolic pathways, over-stimulates the mitogenic pathways and stimulates cell proliferation [23] However, in the present study no association was found between HOMA2-IR and CRC, but this might be due to the small number of cases in the analysis
In the present study, more of the cases than the non-cases developed diabetes They also had a larger waist circumference Some research has suggested that the as-sociation between diabetes and CRC may not be causal; rather the two diseases just share the same precondi-tions, such as obesity [24] This might be a reason why only high glucose levels, and not insulin and insulin re-sistance, show risk association Metformin reduces insu-lin resistance and improves glycaemic control [25] High intake of metformin seems to be protective against CRC [26] The hypothesis is that metformin slows the pro-gression and growth of the tumour [27] In the present study, it was not possible to determine whether metfor-min was used between inclusion and the end of study, and this might have affected the results However, in ex-cluding incident diabetes in the sensitivity analysis, the effect on cancer development might have been avoided, but also excluding those with higher blood glucose, and decreasing the possible number of cases in the analysis
As seen in our previous and present study on the MDCS, associations with CRC might not be straightfor-ward, but may be dependent on sex and cancer site [28] CRC may differ in nature depending on whether it is a distal or proximal CRC, with more micro instability in the distal CRC and more chromosomal instability in the proximal cancer [29] Whether this difference can ex-plain the variations in associations between rectal and
Trang 7colon cancer remains to be determined There is a
differ-ence in the DNA methylation based on sex An
associ-ation between altered expressions and insulin secretion
in the human pancreatic islet has been found, where
women have a higher glucose-induced insulin secretion
[30] Oestrogen also plays an important role in the
glu-cose metabolism in the body Oestrogen facilitates the
transport of glucose to the brain and promotes neural
aerobic glycolysis [31] In men, 5-DHEA, an adrenal
steroid hormone which modulates glucose uptake, is
more elevated than in women [32] As there are
differ-ences in the glucose metabolism for men and women,
high glucose levels may affect the risk differently, as seen
in the present study
The strength of the present research is that it is a
co-hort study with a long follow-up A limitation of the
study is the small number of cases, and it cannot be
ex-cluded that some of the stratified analyses may be
underpowered Taking family history of CRC or
inflam-matory bowel disease into account in our analyses would
have been valuable, since they are contributing factors in
the development of CRC [33], but information on these
risk factors was missing, as was information on family
history of diabetes and blood lipid profile Even if
adjust-ments for possible confounders and known risk factors
were made, the occurrence of some residual
confound-ing cannot be excluded
Conclusion
High levels of blood glucose are associated with risk of
CRC, mainly with colon cancer in men The findings
contribute to facilitating to identify those most in need
of prevention and screening
Abbreviations
AGE: Advanced Glycation End products; BMI: Body Mass Index;
HOMA2-IR: Homeostasis Model Assessment for Insulin Resistance; IGF-1: Insulin-like
Growth Factor 1; MDC-CC: The Cardiovascular Cohort in the Malmö Diet and
Cancer study; MDCS: Malmö Diet and Cancer study; ROS: Reactive Oxygen
Species
Acknowledgments
Professional writing service was provided by Anchor English.
Funding
This study was funded by grants from Development Foundation of Region
Skåne, Direktör Albert Påhlsson ’s Foundation, the Malmö Hospital
Foundation for Cancer Prevention and the South Region of healthcare The
funders had no role in the design, analysis or writing of this article.
Availability of data and materials
The data that supports the finding of this study are available from the Malmö
Diet and Cancer Study, but restrictions apply to the availability of these data,
which are used under license for the current study, and so are not publicly
available Data are however available from the authors upon reasonable request
and with permission of the Malmö Diet and cancer study.
Authors ’ contributions
AV contributed to the study design, performed the data analysis and the
interpretation of the results and wrote the manuscript BO and JM contributed
to the study design and interpretation of the results BO financed the study All authors contributed to the manuscript writing with constructive criticism.
Ethics approval and consent to participate All procedures performed in the studies involving human participants were
in accordance with the ethical standard of the ethical committee at Lund University (50 –91, 2013/804) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Competing interest The authors declare that they have no competing interests.
Consent for publication Not applicable.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author details 1
Lund University, Skåne University Hospital, Department of Clinical Sciences, Division of Internal Medicine, Jan Waldenströms gata 14, 205 02 Malmö, Sweden.2Lund University, Skåne University Hospital, Department of Clinical Sciences, Division of Surgery, Inga Marie Nilssons gata 47, 205 02 Malmö, Sweden.3Lund University, Skåne University Hospital, Department of Clinical Sciences, Division of Internal Medicine, Jan Waldenströms gata 15, 205 02 Malmö, Sweden.
Received: 12 April 2017 Accepted: 4 December 2017
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